(Tutorial chemistry texts 8) malcolm sainsbury, john d hepworth, e w abel, david phillips, j derek woollins heterocyclic chemistry royal society of chemistry (2001)

Pyridine and benzene conform to Hiickel's rule, which predicts that planar cyclic polyenes containing 4n + 2 n-electrons n = 0, or an inte- ger should show added stability over that anti

109 Visual Elements Periodic Table, available at www.chemsoc.org/viselements

ISBN 0-85404-652-6

A catalogue record for this book is available from the British Library

0 The Royal Society of Chemistry 2001

All rights reserved

Apart from any fair dealing for the purposes of research or private study, or criticism or review as permitted under the terms of the UK Copyright, Designs and Patents Act,

1988, this publication may not be reproduced, storedor transmitted, in any form or by

any means, without the prior permission in writing of The Royal Society of Chemistry,

or in the case of reprographic reproduction only in accordance with the terms of the

licences issued by the Copyright Licensing Agency in the UK, or in accordance with the terms of the licences issued by the appropriate Reproduction Rights Organization out-

side the UK Enquiries concerning reproduction outside the terms stated here should be sent to The Royal Society of Chemistry at the address printed on this page

Published by The Royal Society of Chemistry, Thomas Graham House, Science Park,

Milton Road, Cambridge CB4 OWF, UK

Registered Charity No 207890

For further information see our web site at www.rsc.org

Typeset in Great Britain by Wyvern 2 1, Bristol

Printed and bound by Polestar Wheatons Ltd, Exeter

This book provides a concise, yet thorough, introduction to the vast sub- ject of heterocyclic chemistry by dealing only with those compounds con- taining a single heteroatom By restricting the discussion to these, the most important classes of heterocycles, a balanced treatment is possible, allowing the student to rapidly understand the importance of heterocyclic compounds in general to mankind and at the same time stimulating an interest in the challenges this chemistry presents

The contents of the book are carefully designed to meet the needs of undergraduate students in the 2nd year of a degree course in Chemistry

or Biochemistry and are based upon the author’s own lectures given to students at Bath Although primarily an undergraduate text, the main principles that govern heterocyclic chemistry as a whole are addressed in this book, providing a sure foundation for those wishing to widen their

interest in heterocyclic chemistry in later years

Malcolm Sainsbury

Bath

TUTORIAL CHEMISTRY TEXTS

E D I T O R - I N - C H t E F E X E C U T I V E E D I T O R S E D U C A T I 0 N A L C O N S U L T A N T

Professor E W Abel Professor A G Davies

Professor D Phillips Professor J D Woollins

Mr M Berry

This series of books consists of short, single-topic or modular texts, concentrating on the funda- mental areas of chemistry taught in undergraduate science courses Each book provides a concise account of the basic principles underlying a given subject, embodying an independent- learning philosophy and including worked examples The one topic, one book approach ensures that the series is adaptable to chemistry courses across a variety of institutions

T I T L E S 1N T H E S E R I E S F O R T H C O M I N G T I T L E S

Stereochemistry D G Morris

Reactions and Characterization of Solids

Main Group Chemistry W Henderson

d- and f-Block Chemistry C J Jones

Structure and Bonding J Barrett

Functional Group Chemistry J R Hanson

Organotransition Metal Chemistry A F Hill

Heterocyclic Chemistry M Sainsbury

Quantum Mechanics for Chemists

Thermodynamics and Statistical Mechanics

Mechanisms in Organic Reactions

Atomic Structure and Periodicity J Barrett

Bioinorganic Chemistry Chemistry of Solid Surfaces Biology for Chemists Multi-element NMR

Further information about this series is available at www chemsoc orgltct

Orders and enquiries should be sent to:

Sales and Customer Care, Royal Society of Chemistry, Thomas Graham House,

Science Park, Milton Road, Cambridge CB4 OWF, UK

Tel: +44 1223 432360; Fax: +44 1223 426017; Email: sales@rsc.org

I Introduction to Heterocyclic Chemistry

4.3 Pyran-2-ones (a-Pyrones) 4.4 Pyran-4-ones (y-Pyrones) 4.5 Reduced Pyrans

4.6 Saccharides and Carbohydrates

61

63

65

65

5 Benropyrylium Salts, Coumarins,

Chromones, Flavonoids and Related

6 Five-membered Heterocycles containing

One Heteroatom: Pyrrole, Furan and

6.1 Pyrrole 6.2 Furan 6.3 Thiophene

97

110

8 Four-membered Heterocycles containing a

Single Nitrogen, Oxygen or Sulfur Atom 115

8.1 Azete, Azetine and Azetidine 8.2 Oxetene and Oxetane 8.3 Thietene and Thietane

115

121

122

Answers to Problems 125 Subject Index 141

I

Introduction to Heterocyclic

Chemistry

1.1 Coverage

The subject of heterocyclic chemistry is vast, so in this book the focus

is on the more common four-, five- and six-membered systems contain-

ing one heteroatom Little attempt is made to extend the coverage to

more complex heterocycles, so that students interested in extending their

knowledge will need to consult more advanced works Fortunately, there

is a very wide choice; excellent texts include Heterocyclic Chemistry by

Gilchrist' and Heterocyclic Chemistry by Joule and Mills.2 In addition,

there are many authoritative compilations that deal with heterocyclic

chemistry in much more depth?

I .2 Nomenclature

~~

~~

Students will be familiar with carbocyclic compounds, such as cyclo-

hexane and benzene, that are built from rings of carbon atoms If one

or more of the carbon atoms is replaced by another element, the prod-

uct is a heterocycle Multiple replacements are commonplace, and the

elements involved need not be the same The most common are oxygen,

I

sulfur or nitrogen, but many other elements can function in this way, including boron, silicon and phosphorus Chemists have been working with heterocycles for more than two centuries, and trivial names were often applied long before the structures of the compounds were known

As a result, many heterocycles retain these names; a selection of com- mon five- and six-membered heterocycles that contain one oxygen, nitro- gen or sulfur atom are included in Box 1.1 The ring atoms are normally numbered such that the heteroatom carries the lowest number

Some authors use Greek letters,

a, p and y, etc., in place of

numbers, to indicate the position

of substitution in much the same

way that the terms ortho, meta

and para are used for benzenes

A problem arises with trivial names when a sp3 hybridized atom is present

in an otherwise unsaturated ring A good example is pyran, a hetero-

cycle that is formally the product of the addition of a single hydride ion

to the pyrylium cation However, as this addition could occur either at

C-2 or C-4, two isomers of pyran are possible; so the question is, how can you distinguish between them? The solution is to call one compound 2H-pyran and the other 4H-pyran, using the number of the ring atom and the letter H, in italics, to show the position of the hydrogen (see Box 1.2) This system of nomenclature works tolerably well in many related cases and is widely used; other examples will be found in this book

It is also customary to use the prefixes di-, tetra-, hexahydro- (rather than tri-, penta- or heptahydro- ) when referring to compounds that are partly or fully reduced This terminology reflects the fact that hydro- gen atoms are added two at a time during the hydrogenation of multi- ple bonds, and it is used even when the compound contains an odd number of hydrogen atoms relative to its fully unsaturated parent As

before, the position of the ‘extra hydrogen’ atom is located by means of

the ring atom number, followed by the letter H It is important to note

that the lowest possible number is always selected for the locant; so, for

tetrahydro-2H-pyran (see Box 1.2)

abandon them in favour of a logical nomenclature system that provides

structural information Nevertheless, a predictive method of this type is

very desirable, especially for molecules where there may be two or more

Thus, pyridine becomes azabenzene and piperidine is azacyclohexane

This method is useful when dealing with simple heterocycles, but it

can become clumsy with more complex ones An alternative is the

Hantzsch-Widman system, which uses the same prefixes, but adds a stem

name designed to indicate not only the ring size but also the state of

unsaturation or saturation (note: when the stem name begins with a

vowel the last letter, a, of the prefix is dropped) The stem names for

Using this terminology, furan becomes oxole and tetrahydrofuran is

names, the potential difficulty over partly reduced heterocycles is resolved

-

Table 1.1 Hantzsch-Widman stem names for heterocycles with 3-10 ring atoms

Ring size Unsaturated Saturated

by using the usual numbered H prefix; thus, the four possible isomers of

azepine are termed as in Box 1 3.7

For a full discussion of how to

name heterocycles by this and

other methods, see Panico et a/.7

Many heterocycles are fused to other ring systems, notably benzene, giv- ing in this case benzo derivatives; some of these compounds are also extremely well known and have trivial names of their own, such as indole and isoquinoline Here, however, it is possible to relate these compounds back to the parent monocycles by indicating to which face the ring fusion applies To do this, each face of the ring is given a letter (lower case ital- ic), beginning with the face that bears the heteroatom (see Box 1.4)

1.3 Importance to Life and Industry

Many heterocyclic compounds are biosynthesized by plants and animals and are biologically active Over millions of years these organisms have been under intense evolutionary pressure, and their metabolites may be used to advantage; for example, as toxins to ward off predators, or as colouring agents to attract mates or pollinating insects Some heterocy- cles are fundamental to life, such as haem derivatives in blood and the

chlorophylls essential for photosynthesis (Box 1.5) Similarly, the paired

bases found in RNA and DNA are heterocycles, as are the sugars that

in combination with phosphates provide the backbones and determine

the topology of these nucleic acids

Dyestuffs of plant origin include indigo blue, used to dye jeans A poi-

son of detective novel fame is strychnine, obtained from the plant resin

curare (Box 1.6)

The biological properties of heterocycles in general make them one

of the prime interests of the pharmaceutical and biotechnology indus-

tries A selection of just six biologically active pyridine or piperidine

derivatives is shown in Box 1.7 It includes four natural products (nico- tine, pyridoxine, cocaine and morphine) and two synthetic compounds (nifedipine and paraquat)

There are many thousands of other heterocyclic compounds, both nat- ural and synthetic, of major importance, not only in medicine but also

in most other activities known to man Small wonder then that their chemistry forms a major part of both undergraduate and postgraduate curricula

1.4 General Principles

I =4=1 Aromaticity

Many fully unsaturated heterocyclic compounds are described as aro- matic, and some have a close similarity to benzene and its derivatives For example, pyridine (azabenzene) is formally derived from benzene through the replacement of one CH unit by N As a result, the consti-

tutions of the two molecules are closely related: in each molecule all the

ring atoms are sp2 hybridized, and the remaining singly occupied p-

orbital is orientated at right angles to the plane of the ring (orthogonal)

All six p-orbitals overlap to form a delocalized n-system, which extends

as a closed loop above and below the ring

Pyridine and benzene conform to Hiickel's rule, which predicts that

planar cyclic polyenes containing (4n + 2) n-electrons (n = 0, or an inte-

ger) should show added stability over that anticipated for theoretical

polyenes composed of formal alternate single and double bonds This

difference is sometimes called the empirical resonance energy For exam-

ple, benzene, where n = 1, is estimated to be 150 kJ mol-' more stable

than the, hypothetical molecule cyclohexatriene (Box 1.8); for pyridine,

Values for

be obtained in several ways, and when comparisons are being made between one molecule and another the data must be

obtained by the same method of calculation

energy can the empirical resonance energy is 107 kJ mol-'

Alternate double and single bonds are often used in drawing aromatic

structures, although it is fully understood these form a closed loop (n-

system) of electrons The reason is that these classical structures are used

in the valence bond approach to molecular structure (as canonical

course of reactions

The increased stability of 4n + 2 cyclic planar polyenes, relative to

their imaginary classical counterparts, comes about because all the bond-

ing energy levels within the n-system are completely filled For benzene

and pyridine there are three such levels, each containing two spin-paired

electrons There is then an analogy between the electronic constitutions

of these molecules and atoms that achieve noble gas structure

A further result of the delocalization of the p-electrons is the merg-

ing of single and double bonds; benzene is a perfect hexagon with all

C-C bond lengths the same (0.140 nm)

Like benzene, pyridine is hexagonal in shape, but in this case the per-

fect symmetry of the former molecule is distorted because the C-N bonds

If cyclohexatriene were to exist in

a localized form and was a planar

molecule it would contain three

long single bonds and three short

double bonds (in buta-l,3-diene

the C,-C,, bond length is 0.134

nm and the C,-C, bond length is

0.148 nm) The result would be

an irregular hexagon and there

would be two isomers for, say, a

hypothetical 1,2-dichlorocyclo-

hexatriene: one with a single C-C

bond separating the two chlorine

atoms, and the other with a

double C=C bond

are slightly shorter than the C-C bonds (0.134 nm versus 0.139-0.140

nm) This is because nitrogen is more electronegative than carbon, and this fact also affects the nature of the n-system In pyridine the electron density is no longer uniformly distributed around the ring and is con- centrated at the N atom

Another difference between the molecules is that whereas in benzene each carbon is bonded to a hydrogen atom, in pyridine the nitrogen pos- sesses a lone (unshared) pair of electrons This lone pair occupies an sp2 orbital and is orientated in the same plane as the ring; moreover, it is available to capture.a proton so that pyridine is a base

In five-membered heterocycles, formally derived from benzene by the replacement of a CH=CH unit by a heteroatom, aromaticity is achieved

by sharing four p-electrons, one from each ring carbon, with two elec- trons from the heteroatom Thus in pyrrole, where the heteroatom is N, all the ring atoms are sp2 hybridized, and one sp2 orbital on each is bonded to hydrogen To complete the six n-electron system the non- hybridized p-orbital of N contributes two electrons (Box 1.9) It follows that the nitrogen atom of pyrrole no longer possesses a lone pair of elec- trons, and the compound cannot function as a base without losing its aromatic character

I 4.2 Non-aromaticity and Anti-aromaticity

Cyclic polyenes and their heterocyclic counterparts which contain 4n p-electrons do not show aromaticity, since should these molecules be

forced to form a planar array the orbitals used to accommodate the electrons within the closed loop are no longer just bonding in nature,

but a mixture of both bonding and non-bonding types For a fully unsat-

urated planar polyene containing four ring atoms, the number of bond- ing energy levels is one and there are two degenerate non-bonding levels (Box 1.10); in the case of an eight-membered ring, there are three bond- ing sub-levels and two degenerate non-bonding levels

Consider a fully delocalized symmetrical ‘cyclobutadiene’; here each carbon atom is equivalent and sp2 hybridized; this leaves four p-electrons to overlap and to form a n-system Two electrons would then

enter the bonding orbital with their spins paired; however, following

Hund’s rule the other two have to occupy the two degenerate non-

bonding orbitals singly with their spins parallel In essence the result is

a triplet diradical, which is anti-aromatic, i e the result of delocalization

actually leads to a destabilization of the molecule relative to an alterna-

tive model with double and single bonds

It turns out that cyclobutadiene is not a perfect square (two bonds

are longer than the others), but it is essentially planar Not surprising-

ly, it is very unstable and dimerizes extremely readily It only exists at

very low temperatures either in a matrix with an inert ‘solvent’ (where

the molecules are kept apart), or at room temperature as an inclusion

compound in a suitable host molecule Azacyclobutadiene (azete) is also

extremely unstable, for similar reasons

Although a major divergence from planarity is not possible for small

cyclic delocalized polyenes containing 4n electrons, their larger equiva-

lents adopt non-planar conformations Here destabilizing orbital over-

lap between adjacent double bonds is minimized; the compounds are thus

non-aromatic, and their chemistry often resembles that of a cycloalkene

A good example is cyclooctatetraene (Box 1.1 1); formally the higher

homologue of benzene, it is a 4n type containing eight p-electrons This

Hund’s rule states: electrons

enter degenerate orbitals singly with their spins parallel, before pairing takes place The term degenerate here means having the same energy but not the same symmetry or spatial orientation

The term triplet derives from the

three spin states used by a molecule having two unpaired electrons A singlet state is one in which all the electrons are spin- paired, and in principle for every triplet state there is a

corresponding singlet state In most cases the triplet state is more stable than the singlet (also

a consequence of Hund’s rule)

The dianion of cyclooctatetraene

is planar and aromatic in nature

It has two more electrons than its

parent and consequently has 10

x-electrons; it now becomes a

member of the aromatic 4n + 2

series

The absolute frequency of an 'H

NMR signal is not normally

measured; instead,

tetramethylsilane [(CH,),Si, TMS]

is added to the sample as an

internal standard The difference

between the proton resonance of

TMS and that of the sample,

both measured in hertz, divided

by the spectrometer frequency in

megahertz, is called the

chemical shift (given the symbol

8) This is quoted in ppm (parts

per million) To simplify matters

the chemical shift of TMS is

defined as zero Note: the vast

majority of proton resonances

occur downfield from that of

TMS, with values greater than 0

PPm

compound is not planar, it has no special stability and it exists as equil-

The circulating electrons in the n-system of aromatic hydrocarbons

and heterocycles generate a ring current and this in turn affects the chem-

ical shifts of protons bonded to the periphery of the ring This shift is usually greater (downfield from TMS) than that expected for the proton resonances of alkenes; thus 'H NMR spectroscopy can be used as a 'test for aromaticity' The chemical shift for the proton resonance of benzene

and the resonances of the protons of pyridine and pyrrole exhibit the chemical shifts shown in Box 1.12

I 4.3 Ring Strain in Cycloalkanes and their Heterocyclic

Counterparts

Conformation

Although cyclopropane is necessarily planar, this is not the case for other cycloalkanes Cycloalkanes utilize sp3 hybridized carbon atoms, and the

configuration of the bonds Indeed, any deviation from this ideal induces angle strain However, other factors must also be considered; for exam-

angle strain, the chair form is more stable than the boat by approxi-

tion there are serious non-bonded interactions, particularly C-H bond

result, only the chair form is populated at normal temperatures Fully reduced pyridine (piperidine) follows the same pattern and also exists as

Formerly, there was much discussion over how much space a lone pair of electrons occupies relative to a hydrogen atom It now seems clear

stituent increases

equatorial N-H and axial N-H in piperidine is estimated to be 1.5-3.1 kJ mol-1 in favour of the

Components of Ring Strain

Angle and torsional strain are major components of the total ring strain

smaller the ring, the larger the overall strain becomes What may appear

Table 1.2 Ring strain in cycloalkanese

Number of atoms Total strain Number of atoms Total strain

in the ring (kJ mol-l) in the ring (kJ mol-l)

115

110

26 0.5

are considerably more strained than cyclohexane One might think that increased flexibility would be beneficial, but in these cases, although puckering reduces angle strain, many pairs of eclipsed H atoms are also created in adjacent CH, groups These may further interact across the ring, causing compression if they encroach within the normal van der Waals’ radii of the atoms involved (this additional strain is called

‘transannular strain’) However, as more atoms are introduced and the ring size expands, these problems are reduced, and the molecules even- tually become essentially strain free

These considerations may also apply to fully reduced heterocycles, where one or more N or 0 atoms replace ring carbons, but it must be noted that a change in element also means a change in electronegativi-

ty and a change of bond length Thus in hetero analogues of cyclohexa-

ne, for example, as C-N and C-0 bonds are shorter than C-C bonds,

there are increased 1,3- (flagpole) interactions in the chair forms, ren-

dering axial substitution even less favourable

Furthermore, for multiple replacements, lone pair electrons on the heteroatoms may interact unfavourably and limit certain conformations

In fact, interactions between lone pairs are the main reason for increased barriers to rotation, particularly in N-N bonds compared to C-C single bonds

Anomeric Effect

When a ring system contains an O-CH-Y unit, where Y is an elec-

tronegative group (halogen, OH, OR’, OCOR’, SR’, OR’ or NR’R’’),

one of the oxygen lone pairs may adopt a trans antiperiplanar relation-

ship with respect to the C-Y bond (Box 1.14) In this orientation the

orbital containing the lone pair overlaps with the antibonding o orbital

(o*) of the C-Y bond and ‘mixes in’ to form a pseudo n-bond This is

called the anomeric effect When Y is F or Cl (strongly electronegative)

the net result is that the 0-C bond is strengthened and shortened, where-

as the C-Y bond is weakened and lengthened However, for other Y

atoms (e.g oxygen or nitrogen) the anomeric effect can operate in both

directions, i.e Y can be a donor as well as an acceptor

Anomeric effects are cumulative, and can cause a potentially flexible

ring to adjust to a more rigid conformation in order to maximize the

overlap of suitable lone pair and o* orbitals It has been particularly

instructive in explaining ‘anomalous’ preferences for substituent mien- The simply restricted to ring

effect is not

tations in tetrahydropyrans and related compounds, In the case of 2- compounds and a full discussion

methoxytetrahydropyran, for example, the axial conformer is three times ~ e ~ ( ? ~ ~ ~ ~ ‘ ; e ~ n c e ~ ~ for o ~ ~ e ~more populated than the equatorial form (Scheme 1.2)

Nitrogen and oxygen are found in level 2 of the Periodic Table, and a

further alteration in ring topology may arise when the heteroatom is

replaced by an element from a lower level Here, apart from an increase

in atomic diameter, the replacement element may use a hybridization

state different than that of the earlier elements Not only can this affect

the shape of the molecule, it can also modify the chemical properties

conformations where the best donor lone pair, or bond, is orientated antiperiplanar to the best acceptor bond’.g

Scheme 1.2

1 T L Gilchrist, Heterocyclic Chemistry, 2nd edn., LongmanNiley,

4 A R Katritzky and C W Rees (eds.), Comprehensive Heterocyclic

Chemistry, vols 1-8, Pergamon Press, Oxford, 1984

5 A R Katritzky, C W Rees and E F V Scriven (eds.),

Comprehensive Heterocyclic Chemistry 11, A Review of the Literature 1982-1995, vols 1-1 1, Pergamon Press, Oxford, 1996

Elsevier, Amsterdam, 1973-1986 (supplements 1990-2000)

Nomenclature of Organic Compounds (Recommendations 1993),

Blackwell Science, Oxford, 1993

6 Rodds Chemistry of Carbon Compounds, 2nd edn., vols IVA-K,

7 R Panico, W H Powell and J.-C Richer (eds.), A Guide to IUPAC

8 J S Chickos et al., J Org Chem., 1992, 57, 1897

1 9 A J Kirby, The Anomeric Effect and Related Stereoelectronic Effects

I ut Oxygen, Springer, New York, 1983

I

J Rigaudy and S P Klesney (eds.), IUPAC Nomenclature of Organic

Chemistry (Sections A to H ) , Pergamon Press, Oxford, 1979

L A Paquette, Principles of Modern Heterocyclic Chemistry, Benjamin,

New York, 1966

A R Katritzky, Physical Methods in Heterocyclic Chemistry, Academic

Press, New York, 1960-1 972

M J Cook, A R Katritzky and P Linda, Aromaticity of Heterocycles,

in Adv Heterocycl Chem., 1974, 17, 257

D H R Barton and W D Ollis (eds.), Comprehensive Organic

Chemistry, vol 4, Heterocyclic Chemistry, ed P G Sammes,

Pergamon Press, Oxford, 1979

A R Katritzky, M Karelson and N Malhotra, Heterocyclic

Aromaticity, in Heterocycles, 199 1, 32, 127

B Ya Simkin and V I Minkin, The Concept of Aromaticity in

Heterocyclic Chemistry, in Adv Heterocycl Chem., 1993, 56, 303

E L Eliel and S H Wilen, Stereochemistry of Organic Compounds,

Wiley, Chichester, 1994

E Juaristi and G Cuevas, The Anomeric Effect, CRC Press, Boca

Raton, Florida, 1995

Pyridine

A dipole moment results when a

molecule has a permanent

uneven electron density Individual

charge separations in bonds

cannot be measured, only the

vectorial sum of all individual

bond moments A dipole moment

is expressed in debye units (D)

Only completely symmetrical

molecules fail to have a dipole

moment, but few have dipole

moments greater than 7 D

2.1 Resonance Description

As our first more detailed foray into heterocyclic chemistry we will con-

sider pyridine (azabenzene) It is an aromatic compound (see previous

a dipole moment of 2.2 D, denoting a shift of electron density from the ring towards the nitrogen atom (benzene, which is symmetrical, has no dipole moment) The valence bond (resonance) description indicates that the nitrogen atom of pyridine carries a partial negative charge and the

4

Scheme 2.1

18

2.2 Electrophilic Substitution

2.2.1 Attack at Nitrogen and at Carbon

From the resonance description you might conclude that although the

primary site for electrophilic attack is at N-1, reactions at carbon C-3(5)

might be possible, even if not as likely However, an important point to

remember is that the N atom of pyridine carries a lone pair of electrons;

these electrons are NOT part of the n;-system As a result, pyridine is a

base (pKa 5.2), reacting with acids, Lewis acids and other electrophiles

cycle retains aromatic character

0 0 N Y+ -,o N I - 0 N I - o+ N I

Direct attack at a ring carbon, even C-3, is normally slow (a) because

the concentration of free pyridine in equilibrium with the pyridinium salt

is extremely low, and (b) attack upon the salt would also require the pos-

itive pyridinium cation to bond to a positively charged reactant

Indeed, where reactions at a ring carbon take place under relatively

mild conditions, special circumstances are at work For example, 2,6-tert-

butylpyridine combines with sulfur trioxide in liquid sulfur dioxide at

nation is that the bulky tert-butyl groups prevent access of the 'large'

electrophile to N- 1 Steric hindrance is much less at C-3 and sulfonation

is diverted to this site using the 'free' pyridine as the substrate

Scheme 2.2

Pyridinesulfonic acids are strongly acidic, so that the 3-sulfonic acid that forms then protonates a second molecule of 2,6-tert- butylpyridine (N-protonation is permitted because of the small size of the proton) Once protonated, however, further electrophilic attack is strongly disfavoured, and so the overall conversion is limited to 50%

Scheme 2.3

2.2.2 Addition-Elimination

Another feature that is clear from the resonance description of the pyri- dinium cation is that attack by nucleophiles is favoured at C-2(6) and C-4 This has importance in some reactions where at first sight it may appear that electrophilic reagents combine quite easily with pyridine These reactions are more subtle in nature!

For example, 3-bromopyridine is formed when pyridine is reacted with bromine in the presence of oleum (sulfur trioxide in conc sulfuric acid)

at 130 "C (Scheme 2.4) Direct electrophilic substitution is not involved, however, aszwitterionic (dipolar) pyridinium-N-sulfonate is the substrate for an addition of bromide ion Subsequently, the dihydropyridine that

is formed reacts, possibly as a dienamine, with bromine to generate a dibromide, which then eliminates bromide ion from C-2 It is notable that no bromination occurs under similar conditions when oleum is replaced by conc sulfuric acid alone; instead, pyridinium hydrogensul- fate is produced

if mercuric [mercury(II)] sulfate is present as a catalyst (Scheme 2.5) The process is not straightforward and may involve a C-mecuriated pyridine intermediate [it is known, for example, that pyridine reacts with mer- curic acetate at room temperature to form a pyridinium salt that decom- poses at 180 "C into 3-(acetoxymercuri)pyridine (X = OAc)] Without the catalyst, long reaction times and a temperature of 350 "C are neces- sary; even then, the yield of pyridine-3-sulfonic acid is poor

2.2.3 Acylation and Alkylation

Pyridine reacts with acyl chlorides, or acid anhydrides, to form N -

HgX

Scheme 2.5

However, the salts can be used as valuable transacylating agents, par-

ticularly for alcohols, and in this application the salt is not isolated but

reacted in situ with the alcohol An excess of pyridine is needed and such

reactions were carried out in pyridine both as reagent and as solvent

Unfortunately, pyridine is difficult to remove from the products, and its

use has been superseded by DMAP [4-(N, N-dimethy1amino)pyridinel

Now, after N-acylation the 4-N, N-dimethylamino group reinforces the

nucleophilicity of the corresponding acylpyridinium salt (Scheme 2.6b),

and this promotes the transfer of the acyl group from the salt to the alco-

hol in the next step Only a catalytic amount of DMAP is used

R = alkyl or aryl

+

R,oYMe 0

Scheme 2.6

Alkyl halides and related alkylating agents react with pyridines to form

N-alkylpyridinium salts (Scheme 2.7) These compounds are much more

stable than their N-acylpyridinium equivalents and can often be isolat-

ed as crystalline solids, particularly if the halide ion is exchanged for per-

chlorate, tetrafluoroborate or another less polarizable counter anion

Scheme 2.7

Pyridine N-oxide exhibits a dipole

moment of 4.25 D (cf pyridine,

2.2 D) and it is important to note,

however, that because of the

formal positive charge upon the

nitrogen atom, pyridine N-oxides

are also susceptible to

Pyridine N-oxides are frequently used in place of pyridines to facilitate

electrophilic substitution In such reactions there is a balance between electron withdrawal, caused by the inductive effect of the oxygen atom, and electron release through resonance from the same atom in the oppo- site direction Here, the resonance effect is more important, and elec- trophiles react at C-2(6) and C-4 (the antithesis of the effect of resonance

in pyridine itself)

The N-oxide is prepared from pyridine by the action of a peracid (e.g

hydrogen peroxide in acetic acid, forming peracetic acid in situ, or

rn-chloroperbenzoic acid, MCPBA); pyridine is regenerated by de- oxygenation by heating with triphenylphosphine (Ph,P + Ph,PO) (Scheme 2.8)

There is thus a subtlety in the

reactions of pyridine N-oxides

with both electrophiles and

nucleophiles that is not easily

explained

Scheme 2.8

As long as the conditions are selected so that the N-oxygen atom is not irreversibly protonated, reactions with electrophiles give 2- and 4-substituted products Thionyl chloride, for example, gives a mixture of 2- and 4-chloropyridine N-oxides in which the 4-isomer is predominant However, pyridine N-oxide reacts with acetic anhydride first to give 1-acetoxypyridinium acetate and then, on heating, to yield 2- acetoxypyridine through an addition-elimination process (Scheme 2.9a) When a similar reaction is carried out upon the 2,3-dimethyl analogue, the acetoxy group rearranges from N-1 to the C-2 methyl group, at

180 "C, to form 2-acetoxymethyl-3-methylpyridine (possibly as shown in Scheme 2.9b)

Nitration at C-4 occurs with conc sulfuric acid and fuming nitric acid (Scheme 2.1Oa); very little 2-nitropyridine N-oxide is formed, but in cases where the electrophile binds strongly to the oxygen atom of the N-oxide,

further attack occurs at C-3 Thus, pyridine N-oxide is brominated at

70 "C by bromine and oleum to form 3-bromopyridine N-oxide, and

sulfonated by oleum and mercuric sulfate at 240 "C to give pyridine-3-

sulfonic acid N-oxide (Scheme 2 lob)

the negative charge to be

When pyridine is reacted with nucleophiles the attack occurs pre-

ferentially at C-2(6) and/or at c-4, as predicted by the resonance descrip- not permit tion of possible reaction intermediates (Scheme 2.1 1) The problem, sharedwith the Natom

however, is that for unsubstituted pyridines the leaving group is the high-

ly reactive hydride ion So, although the first step in the reaction is favoured, the second step is not Oxygen in the air, or an added oxidant, may ease the situation and serve to oxidize the intermediate to an aro- matic pyridine

2.4.2 Chichibabin Reaction

A classic reaction of this type is Chichibabin amination, leading mainly

to 2-aminopyridine (Scheme 2.12a) This takes place when a pyridine is heated at 140 "C with sodamide (NH, is a very strong nucleophile) Although hydrogen gas is certainly evolved during the reaction, the ini- tial proton donor is not known However, once some 2-aminopyridine

is formed this product could function as the donor (Scheme 2.12b), and the process may then become a form of chain reaction

0 N

2.4.3 Nucleophilic Reactions of Halopyridines

Halide Ion versus Hydride Ion

Normally, nucleophilic attack occurs preferentially at C-2(6); this selec-

tivity is the result of the enhancedinductive effect experienced by the

carbon atoms immediately adjacent to the more electronegative nitrogen

(Scheme 2.13) If both C-2 and C-6 are occupied, then attack at C-4

takes place However, it is possible to influence the site and rate of the

reaction if a potential leaving group replaces hydrogen After addition,

the loss of the leaving group from the o-intermediate will be easier than

if it were the very reactive hydride ion Halopyridines are often used,

although not exclusively, and this normally ensures preferential nucle-

ophilic substitution at the site of the halogen atom

c1

very strongly favoured

c1

I Scheme 2.13

‘Addition-substitution’ easily occurs with a variety of nucleophilic

reagents, including NaOMe, PhSH, PhNHMe and NH, Thus, with 2-

chloropyridine a range of 2-substituted pyridines is formed (Scheme

2.14)

Scheme 2.15

2.4.4 Pyridynes

There is a complication if the nucleophile used in reactions with

halopyridines is also a strong base; for now the formation of a pyridyne

is possible, and with sodamide in liquid ammonia (providing the N H z

ion?, B), for example, both 3-aminopyridine and 4-aminopyridine are

This occurs because 3-pyridyne (3,4-didehydropyridine) is formed by an

ElcB process [elimination (first order) from the conjugate base]

An alternative addition of NH; to 3-pyridyne,

bv Drotonation as the

is the

,

3-Pyridyne then adds ammonia; the addition is not regiospecific and two

amino derivatives are formed

second step

285 Lithiation

Scheme 2.1 7

Normally, compounds containing

a methine group situated next to

a carbonyl group (CH-CO) are in

equilibrium with an enol tautomer

which contains the C=C(OH)

group The term enolate anion

refers to the resonance-stabilized

anion, formed by deprotonating

the enol tautomer with a

sufficiently strong base:

with butyllithium The lithium derivatives then behave in a similar man- ner to arylithiums and Grignard reagents and react with electrophiles such as aldehydes, ketones and nitriles (Scheme 2.17) Thus, aldehydes and ketones form alcohols, and nitriles yield N-lithioimines, which on hydrolysis are converted into pyridyl ketones

R OH

2.6 Methods of Synthesis

2.6.1 Hantzsch Synthesis

The most used route to pyridines is called the Hantzsch synthesis This

uses a 1,3-dicarbonyl compound, frequently a 1,3-keto ester [ethyl ace- toacetate (ethyl 3-oxobutanoate)], and an aldehyde, which are heated together with ammonia (Scheme 2.18) At the end of the reaction the dihydropyridine is oxidized to the corresponding pyridine with nitric acid (or another oxidant such as MnO,) The normal Hantzsch procedure leads to symmetrical dihydropyridines Two different 1,3-dicarbonyl compounds may not be used as two enolate anions might form, giving mixed products when reacted with the aldehyde The aldehyde itself should preferably be non-enolizable, otherwise the chance of aldoliza- tion exists, but with care this can be avoided

2.6.2 Guareschi Synthesis

This is a similar synthesis in which the ring atoms are assembled by react- ing a 1,3-dicarbonyl compound with cyanoacetamide (cyanoethanamide)

under mildly basic conditions (Scheme 2.19) The product, a 3-cyano-2-

pyridone, may then be hydrolysed and decarboxylated, before the oxy-

gen atom of the carbonyl group is removed in two steps: by chlorination

Scheme 2.18

Me J$ +H2NJr-Mehr H H2S04aq*- Le&j H

Me f j -Me5(cl= Me ho H

1 4 0 2

2.7 Commonly Encountered Pyridine Derivatives

The chemical behaviour of many substituents attached to the pyridine

ring is similar to that of the corresponding groups in benzene, with the

proviso that resonance with, and the inductive influence of, the ring nitro-

gen atom may significantly modify some reactions

2.7.1 Methylpyridines (Picolines)

These have the trivial generic name picolines; on oxidation they give the

appropriate acids; pyridine-2- and -4-carboxylic acids are called 2- and

4-picolinic acids, respectively (see Box 2.1) Pyridine-3-carboxylic acid is better known as nicotinic acid (reflecting its relationship to the alkaloid

nicotine, see Section 1.3)

2-Picoline and 4-picoline are easily deprotonated as the conjugate car- banions are resonance stabilized These anions can be used in alkylations and other reactions with electrophiles (Scheme 2.20)

Scheme 2.21

The tautomeric preferences

observed for hydroxy and amino

heterocycles is a complex subject

and not always easily

explained .1#2

2.7.2 Pyridones (Hydroxypyridines) Tautomerism

2-Hydroxy- and 4-hydroxypyridines are in tautomeric equilibrium with

isomers bearing a carbonyl group (Scheme 2.22) These are called 2- and 4-pyridones, respectively The pyridone forms are favoured in ionic sol-

vents and also in the solid state

H

2-Pyridone

H

4-Pyridone Scheme 2.22

3-Hydroxypyridine adopts a dipolar (zwitterionic) constitution in polar solvents (Scheme 2.23)

Scheme 2.23

4-Pyridones can be considered to

react with electrophiles at C-3

either as enamines or as enols

H

E~ N

H

Note that 0-Si bonds are

stronger than N-C bonds

mixture of 0- and N-acetyl-4-pyridones, whereas phosphorus oxychlo- ride, together with phosphorus pentachloride, reacts at oxygen and forms

a good leaving group (possibly C1,OPO-), which is then displaced by chloride ion to afford a chloropyridine (Scheme 2.24)

Deprotonation of 2- and 4-pyridones is easily achieved, and the anions react with carbon electrophiles, such as carbon dioxide and trimethyl- silylmethyl chloride, at nitrogen, but with trimethylsilyl chloride at oxygen (Scheme 2.25)